Significance Recapitulating human blood cancers in vitro remains challenging due to the limitations of current models to culture patient-derived malignant hematopoietic stem and progenitor cells in entirely human bone marrow microenvironments. We demonstrate that progenitor cells from patients with acute myeloid leukemia and myeloproliferative neoplasms can be cultured for at least 3 wk in fully human cell-based three-dimensional osteoblastic niches engineered in perfusion bioreactors, while exhibiting key features found in native bone marrow. Furthermore, the system can be customized to include a human vascular component within the engineered stromal microenvironment, which enables investigation of human leukemogenesis under designed settings. This platform can be used to test the effectiveness of chemotherapy compounds, toward application in patient-personalized medicine.